Prophylactic cranial irradiation (PCI) has been used in patients with small cell lung cancer (SCLC) to reduce the high risk (~60%) of brain metastases in these patients. Early trials on PCI have focused on patients in complete remission after treatment for limited stage (LS) disease. Individual studies showed unequivocally a significant reduction in the risk of brain metastases, but a statistically significant survival benefit was only seen in a meta-analysis [1]. In this analysis, an absolute increase in survival rate of 5.4% at 3 years was observed[1]. The vast majority of patients in these studies had a complete remission (often based on chest radiographs) after chemotherapy. Based on these studies, PCI became part of standard treatment of LS-SCLC patients with a complete response. To reduce the risk of neurocognitive toxicity, PCI was not simultaneously given with chemotherapy and started within 6 weeks after last chemotherapy. A study on the effectiveness of higher dose PCI (36 Gy) showed no benefit over standard dose (25 Gy) PCI [2].
Since most patients with SCLC present with extensive stage (ES) disease, and the risk of brain metastases is even higher in this group of patients, the EORTC performed a study on PCI in patients with any response after chemotherapy for ES-SCLC. In this trial, PCI not only significantly reduced the risk of symptomatic brain metastases (15 vs 40%), but also significantly improved survival (1 year survival 27 vs 13%) [3]. This study was pragmatic and in line with existing guidelines not to repeat brain imaging and to focus on symptomatic disease. It was argued that some individuals with asymptomatic, but radiologically detectable brain metastases may have been included in the study and that could, at least partially, have contributed to the outcome. In a Japanese study on PCI in ES-SCLC patients, all patients had a brain MRI to excluded presence of asymptomatic brain metastases [4]. In addition, regular brain MR imaging was performed during follow-up and when appropriate, brain metastases that appeared were treated. The study showed a significant reduction in the rate of brain metastases when using PCI (33 vs 59%), but no survival benefit. In the observation arm that did not receive PCI, many patients (83%) who developed brain metastases were treated with radiotherapy [4]. A SWOG trial (SWOG 1827/”MAVERICK”) has opened in 2020 to compare a strategy of MRI surveillance with early treatment to MRI surveillance with PCI. Interestingly, this study is not only enrolling patients with ES-SCLC but also with LS-SCLC.
In it well known that the disease SCLC and PCI can be associated with cognitive decline. Studies aiming at sparing brain regions involved in memory and cognitive functions, esp. hippocampal region, led to attempt of using hippocampal avoiding PCI (HA-PCI). Whole brain radiotherapy with hippocampal avoidance was associated with better preservation of memory and quality of life [5]. Studies on the benefit of HA-PCI are less conclusive [6,7] and the results of an ongoing trails (NRG CC003) are awaited.
In conclusion, PCI is very effective in reducing the risk of brain metastases in SCLC. There are questions whether the beneficial effect on survival is maintained in the era of MR screening and MR surveillance with early treatment of (asymptomatic) brain metastases. Studies to re-evaluate the role of PCI in the current era of immunotherapy are underway. In the meantime, PCI or MRI surveillance should be considered guideline-recommended treatment. In NSCLC, the role of PCI was also addressed in a number of studies. In a recent trial with long term follow-up (NRG/RTOG0214) and a meta-analyses, earlier findings of a significant reduction in the rate of brain metastases, improvement in disease-free survival, but absence of improved overall survival after PCI, were confirmed [8,9].
Literature
1. Auperin A, Arriagada R, Pignon JP, et al. N Engl J Med 341, 476-84, 1999.
2. Le Pechoux C, Dunant A, Senan S, et al. Lancet Oncol 10, 467-74, 2009.
3. Slotman BJ. Faivre-Finn C, Kramer G, et al. N Engl J Med 357, 664-72, 2007.
4. Takahashi T, Yamanaka T, Seto T, et al. Lancet Oncol 18, 663-71, 2017.
5. Gondi V, Pugh SL, Tome WA. J Clin Oncol 3, 3810-6, 2014.
6. De Dios ND, Counago F, Lopez JL, et al., Int J Radiat Oncol Biol Phys 105, S35-6, 2019.
7. Belderbos JS, De Ruysscher DK, de Jaeger K, et al. T Thor Oncol 16, 840-9, 2021.
8. Sun A, Hu C, Wong SJ. JAMA Oncol 5, 847-55, 2019.
9. Witlox WJA, Ramaekers BLT, Lacas B, et al., Radiother Oncol. 158, 40-7. 2021.